Oral mucositis (OM) is a common side effect in oncology patients receiving radiation treatment. Mucosal breakdown causes pain which leads to increased use of narcotic analgesics and restriction of food intake. OM often progresses to septicemia, increasing hospital stays and costs, and ultimately discontinuation of radiotherapy. This impacts overall effectiveness of cancer therapy so development of an agent for prevention and treatment of OM is clearly an unmet need. Terapio is developing a drug, RLIP76-Proteoliposome (RLIP76-PL), as a radiation countermeasure. When administered systemically, RLIP76-PL dramatically improves survival in a mouse model of whole body radiation, leading to the hypothesis that it could be beneficial as a local application in treating specific radiation toxicities such as OM. This proposed research will test that hypothesis. In Specific Aim #1, the current formulation of RLIP76-PL will be modified to be used as a topical mouthwash. In Aim #2, the efficacy of the topical formulation of RLIP76-PL will be tested in a hamster model to evaluate its effectiveness in reducing the severity of OM after irradiation. Finally, in Specific Aim #3, systemic absorption of mucosally-applied RLIP76-PL will be investigated to guide future studies in a tumor model to establish that RLIP76-PL is not tumor-protective.